The pandemic potential of the Asian Influenza A H5N1 virus is one of the foremost international public health concerns of the 21st century. Ten probable and three possible pandemics have occurred in the past four-hundred years, with an average ten to forty year interpandemic interval. Our last pandemic occurred thirty-nine years ago. The exact timing of the next pandemic remains uncertain, but the fact that one will occur is not. In an interconnected modern world where infectious disease can be transmitted globally in a matter of hours, the WHO estimates that an H5N1 pandemic could cause hundreds of millions of deaths and the World Bank predicts a lasting and crippling impact on global economies could result, with losses of up to $4.4 trillion. While literature exists on public health strategies for current, epidemic, and pandemic Influenza A H5N1 infection scenarios, several important gaps remain. These include evaluating the safety, effectiveness and cost-effectiveness of potential strategies for responding to a pandemic. This project aims to build on my ongoing work in the field of pandemic influenza by: 1. Examining the long-term safety and effectiveness of extended prophylaxis with neuraminidase inhibitors by performing a systematic review and meta-analysis. 2. Assessing the health outcomes, costs and cost-effectiveness of alternative strategies of response in a pandemic, including prophylaxis with neuraminidase inhibitors, prophylaxis with a promising new primeboost vaccination strategy, prophylaxis with masks and N-95 respirators, and no prophylaxis. Our world today differs from that of the devastating 1918 influenza pandemic not only in our global connections and the potential for rapid spread of an influenza virus, but also in our scientific advancements, knowledge, and international cooperation. As we observe Influenza A H5N1 spreading among avian, swine, feline, and canine species, and developing ongoing mutations which increase its ability to infect humans, we have an opportunity that physicians, scientists, and public health officials of 1918 did not. The results of these aims will add to the pandemic influenza literature by establishing safe, effective, and cost-effective strategies which will assist public health officials in preparing for this eventual threat.